Biallelic inactivation of the NF1 tumour suppressor gene in juvenile myelomonocytic leukaemia: genetic evidence of driver function and implications for diagnostic workup

Abstract: Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF-1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild-type allele. Here we examined the two-hit concept in leukaemic cells of 25 patients with JMML and NF-1. Ten patients with JMML/NF-1 exhibited a NF1 loss-of-function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound-heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF-1 and no variation in the JMML-associated driver genes PTPN11, KRAS, NRAS or CBL (JMML-5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound-heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF-1 reliably indicates a NF1-driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF-1

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: British journal of haematology. - 204, 2 (2024) , 595-605, ISSN: 1365-2141

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2023
• Creator: Ramamoorthy, Senthilkumar ; Lebrecht, Dirk ; Geoffroy, Andrieux ; Metzger, Patrick ; Hess, Maria Elena ; Erlacher, Miriam ; Vinci, Luca ; Wlodarski, Marcin W. ; Yoshimi-Nöllke, Ayami ; Börries, Melanie ; Niemeyer, Charlotte ; Flotho, Christian

Further information

• DOI: 10.1111/bjh.19190
• URN: urn:nbn:de:bsz:25-freidok-2411978
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:29 AM CEST